5.1 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess

Abiraterone acetate can lead to increased blood pressure, lowered potassium levels in the blood, and fluid accumulation due to elevated mineralocorticoid levels, which occur as a result of CYP17 enzyme inhibition (refer to Clinical Pharmacology for more details). It's essential to regularly monitor patients for these conditions, ideally once a month. Before initiating and during the course of treatment with abiraterone acetate, controlling high blood pressure and correcting low potassium levels is necessary.

In an analysis of data from four placebo-controlled studies, where patients were given 5 mg of prednisone twice daily along with 1,000 mg of abiraterone acetate daily, it was found that severe hypokalemia (grades 3-4) occurred in 4% of patients treated with abiraterone acetate, compared to 2% in the placebo group. Similarly, severe hypertension (grades 3-4) was observed in 2% of patients in both the abiraterone acetate and placebo groups, and significant fluid retention (grades 3-4) was seen in 1% of patients in each group.

In the LATITUDE trial, a randomized, placebo-controlled, multicenter clinical study, patients were treated with 5 mg of prednisone daily alongside 1,000 mg of abiraterone acetate daily. In this trial, severe hypokalemia (grades 3-4) was found in 10% of patients receiving abiraterone acetate and 1% of those on the placebo. Severe hypertension (grades 3-4) was observed in 20% of patients on the abiraterone acetate arm compared to 10% on the placebo arm, while significant fluid retention (grades 3-4) was reported in 1% of patients in both groups.

Patients with medical conditions that could be exacerbated by increased blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent heart attacks, cardiovascular diseases, or ventricular arrhythmias, should be monitored closely. Postmarketing reports have shown that QT prolongation and Torsades de Pointes can occur in patients who develop hypokalemia while on abiraterone acetate treatment.

The safety of abiraterone acetate in patients with a left ventricular ejection fraction below 50% or with heart failure classified as New York Heart Association (NYHA) Class III or IV (in the COU-AA-301 trial) or NYHA Class II to IV (in the COU-AA-302 and LATITUDE trials) is not established, as these patients were not included in these randomized clinical studies (refer to Clinical Studies for more information).

5.2 Adrenocortical Insufficiency

In a combined analysis of five randomized, placebo-controlled clinical studies, adrenal insufficiency was observed in 0.3% of the 2,230 patients treated with abiraterone acetate, compared to 0.1% of the 1,763 patients receiving a placebo. Instances of adrenocortical insufficiency have been reported among patients taking abiraterone acetate in conjunction with prednisone, particularly after stopping daily steroid use and/or during times of concurrent infection or stress.

It is important to vigilantly monitor for symptoms and indicators of adrenocortical insufficiency, especially when patients stop taking prednisone, undergo reductions in their prednisone dosage, or are under unusual stress. The symptoms and signs of adrenocortical insufficiency may be obscured by side effects related to mineralocorticoid excess that are common in patients undergoing treatment with abiraterone acetate. If adrenocortical insufficiency is suspected, appropriate diagnostic tests should be conducted to confirm the condition. In situations of stress, before, during, and after, an increase in corticosteroid dosage might be necessary (refer to Warnings and Precautions for more details).

5.3 Hepatotoxicity

In the postmarketing phase, severe liver toxicity linked to abiraterone acetate, including cases of fulminant hepatitis, acute liver failure, and fatalities, have been reported (refer to Adverse Reactions for details).

From an analysis of five randomized clinical trials, significant increases in ALT or AST levels (at least five times the upper limit of normal, ULN) were observed in 6% of the 2,230 patients treated with abiraterone acetate, most often within the first three months of starting treatment. Patients with pre-existing elevated ALT or AST levels were at a higher risk of further liver test elevations compared to those with normal baseline values. Due to increases in ALT and AST or abnormal liver function, 1.1% of the 2,230 patients on abiraterone acetate discontinued treatment. No deaths directly attributed to abiraterone acetate due to hepatotoxicity were reported in these trials.

Before initiating abiraterone acetate treatment, measure serum transaminases (ALT and AST) and bilirubin levels, then every two weeks for the first three months and monthly thereafter. For patients with moderate hepatic impairment at baseline and taking a reduced dose of 250 mg abiraterone acetate, check ALT, AST, and bilirubin levels before starting treatment, then weekly for the first month, every two weeks for the next two months, and monthly after that. If signs of hepatotoxicity appear, promptly test for serum total bilirubin, AST, and ALT. Increased monitoring is advised if AST, ALT, or bilirubin levels rise from the patient's baseline. Interrupt abiraterone acetate treatment if AST or ALT levels exceed five times the ULN, or if bilirubin exceeds three times the ULN, and closely monitor liver function.

Consider resuming abiraterone acetate at a reduced dose only after liver function tests return to the patient's baseline or to AST and ALT levels less than or equal to 2.5 times the ULN and total bilirubin less than or equal to 1.5 times the ULN (refer to DOSAGE AND ADMINISTRATION section 2.4 for guidelines).

Permanently discontinue abiraterone acetate for patients who experience simultaneous elevations in ALT greater than three times the ULN and total bilirubin greater than two times the ULN without biliary obstruction or other explainable causes (see Dosage and Administration section 2.4).

The safety of restarting abiraterone acetate in patients who experience AST or ALT levels equal to or greater than 20 times the ULN and/or bilirubin levels equal to or greater than 10 times the ULN is not established.

5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride

Abiraterone acetate plus prednisone/prednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials.

The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone.

5.5 Embryo-Fetal Toxicity

The safety and efficacy of abiraterone acetate have not been established in females. Based on animal reproductive studies and mechanism of action, abiraterone acetate can cause fetal harm and loss of pregnancy when administered to a pregnant female. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with abiraterone acetate and for 3 weeks after the last dose of abiraterone acetate [ SEE USE IN SPECIFIC POPULATIONS (8.1, 8.3)]. Abiraterone acetate should not be handled by females who are or may become pregnant [ SEE HOW SUPPLIED/STORAGE AND HANDLING (16)].

5.6 Hypoglycemia

Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [SEE DRUG INTERACTIONS. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone acetate. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.